Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
Nitric Oxide. 2018 Aug 1;78:72-80. doi: 10.1016/j.niox.2018.05.009. Epub 2018 May 31.
Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC), an enzyme that catalyzes the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophophate (cGMP), transduces many of the physiological effects of the gasotransmitter NO. Upon binding of NO to the prosthetic heme group of sGC, a conformational change occurs, resulting in enzymatic activation and increased production of cGMP. cGMP modulates several downstream cellular and physiological responses, including but not limited to vasodilation. Impairment of this signaling system and altered NO-cGMP homeostasis have been implicated in cardiovascular, pulmonary, renal, gastrointestinal, central nervous system, and hepatic pathologies. sGC stimulators, small molecule drugs that synergistically increase sGC enzyme activity with NO, have shown great potential to treat a variety of diseases via modulation of NO-sGC-cGMP signaling. Here, we give an overview of novel, orally available sGC stimulators that Ironwood Pharmaceuticals is developing. We outline the non-clinical and clinical studies, highlighting pharmacological and pharmacokinetic (PK) profiles, including pharmacodynamic (PD) effects, and efficacy in a variety of disease models.
一氧化氮（NO）-敏感可溶性鸟苷酸环化酶（sGC）是一种酶，可催化鸟苷-5'-三磷酸（GTP）转化为环鸟苷-3'，5'-单磷酸（cGMP），传递气体递质 NO 的许多生理作用。当 NO 与 sGC 的辅基血红素结合时，会发生构象变化，导致酶的激活和 cGMP 的产生增加。cGMP 调节几种下游细胞和生理反应，包括但不限于血管舒张。该信号系统的损害和 NO-cGMP 动态平衡的改变与心血管、肺、肾、胃肠道、中枢神经系统和肝脏疾病有关。sGC 激动剂是一种小分子药物，可与 NO 协同增加 sGC 酶活性，通过调节 NO-sGC-cGMP 信号，显示出治疗多种疾病的巨大潜力。在这里，我们概述了 Ironwood 制药公司正在开发的新型口服 sGC 激动剂。我们概述了非临床和临床研究，突出了药理学和药代动力学（PK）特征，包括药效学（PD）效应，以及在各种疾病模型中的疗效。
